Histamine induces activation of protein kinase D that mediates tissue factor expression and activity in human aortic smooth muscle cells

Abstract

Hao F, Wu DD, Xu X, Cui M. Histamine induces activation of protein kinase D that mediates tissue factor expression and activity in human aortic smooth muscle cells. Am J Physiol Heart Circ Physiol 303: H1344 -H1352, 2012. First published September 21, 2012; doi:10.1152/ajpheart.00500.2011.-Histamine, an inflammatory mediator, has been shown to influence the pathogenesis of vascular wall cells. However, the molecular basis of its influence is not well understood. Our data reveal that histamine markedly induces protein kinase D (PKD) activation in human aortic smooth muscle cells. PKD belongs to a family of serine/threonine protein kinases, and its function in vascular disease is largely unknown. Our data show that histamine-induced PKD phosphorylation is dependent on the activation of histamine receptor 1 and protein kinase C (PKC). To determine the role of PKD in the histamine pathway, we employed a smallinterfering RNA approach to downregulate PKD expression and found that PKD1 and PKD2 are key mediators for expression of tissue factor (TF), which is the key initiator of blood coagulation and is important for thrombosis. Our results show that PKD2 predominantly mediates histamine-induced TF expression via the p38 mitogenactivated protein kinase (MAPK) pathway, whereas PKD1 mediates histamine-induced TF expression through a p38 MAPK-independent pathway. We demonstrate that histamine induces TF expression via the PKC-dependent PKD activation. Our data provide the first evidence that PKD is a new component in histamine signaling in live cells and that PKD has a novel function in the histamine signaling pathway leading to gene expression, as evidenced by TF expression. Importantly, our data reveal a regulatory link from histamine to PKD and TF, providing new insights into the mechanisms of coagulation and the development of atherothrombosis. histamine receptor; protein kinase activation; phosphorylation; tissue factor; vascular wall cells HISTAMINE IS A SMALL MOLECULE amine that is mainly produced by histidine decarboxylase (HDC) from mast cells and monocyte-derived macrophages (18,32). HDC is found in macrophage-derived foam cells (10), and HDC knockout mice show reduced neointimal thickening (22), suggesting a role of histamine in the development of vascular disease.As a potent inflammatory molecule, histamine increases blood vessel permeability and endothelial dysfunction (21, 26) and induces relaxation (15, 36) and constriction (13) of blood vessels. Through the cross talk between calcium flow and mitogen-activated protein kinase (MAPK) induction, histamine may be a risk factor for hypertension (5). Histamine exerts its function through its four receptors (32). We reported previously that histamine induces expression of the master transcription factor Egr-1 in human aortic endothelial cells (8). Histamine also induces tissue factor (TF) expression in smooth muscle cells (SMCs) related to acute coronary syndrome (27). In addition, histamine increases the expression of cytokines such as interleukin (IL)-6 and IL-...

NPY/Y1 receptor‐mediated vasoconstrictory and proliferative effects in pulmonary hypertension

“…PKD has already been implicated in pathological vascular hypertrophy by inactivating the histone deacetylase HDAC5 (Xu et al ., ) and promoting vascular smooth muscle cell proliferation by ERK5 and c‐Fos activation (Geng et al ., ). Furthermore, increased phosphorylation of p38 MAPK could be mediated by PKD (Hao et al ., ). Finally, activation of p38 could additionally lead to attenuated cAMP formation in hPASMC (El‐Haroun et al ., ), a contributing mechanism in NPY vasoconstrictive action.…”

Differential function and regulation of orphan nuclear receptor TR3 isoforms in endothelial cells

“…Lahouaria Hadri et al reported that histamine enhances the promoter activity and expression of SERCA 3 gene via H1 receptor by Ca 2+ -calcineurin pathway in HUVEC-derived EA.hy926 cells [51]. Further studies suggested that PKD and ERK are downstream targets of PLC-PKC to play a role in histamine signaling pathway because (1) histamine induces tissue factor expression via H1 receptor to activate PKC-PKD phosphorylation in smooth muscle cells [52], (2) histamine induces the expression of early growth response factor 1 (Egr-1) by PKC-ERK, and (3) ERK is essential for histamine-induced cytokine production [53, 54]. Our data indicate that TR3-TV2 and TR3-TV3 are regulated by PLC/Ca 2+ /calcineurine/PKC/PKD/ERK signaling pathway via G protein-coupled histamine receptor H1.…”

The role of endocardial endothelium in the effect of histamine on myocardial contractions of histamine H1 and H2 receptor blockade

“…Identifikacija subtipova histaminskih receptora u ljudskom srcu i endotelnim ćelijama obezbeđuje bolje razumevanje uloge histamina u patofiziologiji kardiovaskularnog sistema i doprinosi novom pristupu histaminom izazvanoj srčanoj disfunkciji. Tako, histamin indukuje hiperplaziju intime i promoviše formiranje aterosklerotskih lezija [11], povećava ekspresiju i aktivaciju tkivnog faktora koji je ključni inicijator koagulacije krvi [12] i povećava vaskularnu peremeabinost za LDL [13]. Antagonisti H 1 receptora mogu da imaju kardiotoksični efekat i da inhibiraju repolarizaciju K+ kanala (posebno Ikr) što dovodi do prolongiranja akcionog potencijala [14].…”